Resting state fMRI
Resting state fMRI (rsfMRI or R-fMRI) is a powerful method of functional brain imaging that can be used to evaluate regional interactions that occur when a subject is not performing an explicit task.Biswal, B. B. (2012). Resting state fMRI: A personal history. Review. Neuroimage, 62(2), p. 938-944. This resting brain activity is observed through changes in blood flow in the brain which creates what is referred to as a Blood Oxygen Level Dependent Signal (BOLD) that can be measured using functional Magnetic Resonance Imaging (fMRI). Because brain activity is present even in the absence of an externally prompted task, any brain region will have spontaneous fluctuations in BOLD signal. The resting state approach is useful to explore the brain’s functional organization and to examine if it is altered in neurological or psychiatric diseases. Resting-state functional connectivity research has revealed a number of networks which are consistently found in healthy subjects and represent specific patterns of synchronous activity.Biswal, B. B. (2011). Resting State Functional Connectivity. Biological Psychiatry, 69(9), 200S-200S.Rosazza, C., & Minati, L. (2011). Resting-state brain networks: literature review and clinical applications. Neurol Sci, 32(5), 773-785. Basics of fMRI Functional magnetic resonance imaging (functional MRI or fMRI) is a specific magnetic resonance imaging (MRI) procedure that measures brain activity by detecting associated changes in blood flow. More specifically, brain activity is measured through low frequency BOLD signal in the brain.DeYoe, E. A., Bandettini, P., Neitz, J., Miller, D., & Winans, P. (1994). Functional magnetic resonance imaging (FMRI) of the human brain. J Neurosci Methods, 54(2), 171-187. The procedure is similar to MRI but uses the change in magnetization between oxygen-rich and oxygen-poor blood as its basic measure. This measure is frequently corrupted by noise from various sources and hence statistical procedures are used to extract the underlying signal. The resulting brain activation can be presented graphically by color-coding the strength of activation across the brain or the specific region studied. The technique can localize activity to within millimeters but, using standard techniques, no better than within a window of a few seconds.Bandettini, P. A. (2009). Seven topics in functional magnetic resonance imaging. J Integr Neurosci, 8(3), 371-403. FMRI is used both in research, and to a lesser extent, in clinical settings. It can also be combined and complemented with other measures of brain physiology such as EEG and NIRS. Newer methods which improve both spatial and time resolution are being researched, and these largely use biomarkers other than the BOLD signal. Some companies have developed commercial products such as lie detectors based on fMRI techniques, but the research is not believed to be ripe enough for widespread commercialization.Bandettini, P. (2007). Functional MRI today. Int J Psychophysiology, 63(2), 138-145. Physiological basis The physiological blood-flow response largely decides the temporal sensitivity, how well we can measure when neurons are active, in BOLD fMRI. The basic time resolution parameter is the sampling rate, or TR, which dictates how often a particular brain slice is excited and allowed to lose its magnetization. TRs could vary from the very short (500 ms) to the very long (3 seconds). For fMRI specifically, the haemodynamic response lasts over 10 seconds, rising multiplicatively (that is, as a proportion of current value), peaking at 4 to 6 seconds, and then falling multiplicatively. Changes in the blood-flow system, the vascular system, integrate responses to neuronal activity over time. Because this response is a smooth continuous function, sampling with ever-faster TRs does not help; it just gives more points on the response curve obtainable by simple linear interpolation anyway. Experimental paradigms such as staggering when a stimulus is presented at various trials can improve temporal resolution, but reduces the number of effective data points obtained.Huettel, S. A.; Song, A. W.; McCarthy, G. (2009), Functional Magnetic Resonance Imaging (2 ed.), Massachusetts: Sinauer, ISBN 978-0-87893-286-3 While fMRI strives to measure the neuronal activity in the brain, the BOLD signal can be influenced by many other physiological factors other than neuronal activity. For example, respiratory fluctuations and cardiovascular cycles can affect the BOLD signal being measured in the brain and therefore should be regressed out during processing of the raw fMRI data. Due to these sources of noise, there have been many experts who have approached the idea of resting state fMRI very skeptically during the early uses of fMRI. It has only been very recently that researchers have become confident that the signal being measured is not an artifact caused by other physiological function.Damoiseaux, J. S., Rombouts, S., Barkhof, F., Scheltens, P., Stam, C. J., Smith, S. M., et al. (2006). Consistent resting-state networks across healthy subjects. Proceedings of the National Academy of Sciences of the United States of America, 103(37), 13848-13853. History Bharat Biswal ' :Fifteen years ago (1995) as a graduate student at The Medical College of Wisconsin, Dr. Biswal, while working under the direction of his advisor, James S. Hyde, discovered that the brain, even during rest, contains information about it's functional organization. He had used fMRI to study how different regions of the brain communicate while the brain is at rest and not performing any active task. Though at the time, Dr. Biswal’s research was mostly disregarded and attributed to another signal source, his resting neuroimaging technique has now been widely replicated and considered a valid method of mapping functional brain networks. Mapping the brain’s activity while the body is at rest holds many potentials for brain research and even helps doctors diagnose various diseases of the brain. 'Marcus Raichle :Experiments by neurologist Marcus E. Raichle's lab at Washington University School of Medicine and other groups showed that the brain's energy consumption is increased by less than 5% of its baseline energy consumption while performing a focused mental task. These experiments showed that the brain is constantly active with a high level of activity even when the person is not engaged in focused mental work (the resting state). His lab has been primarily focused on finding the basis of this resting activity and is credited with many ground breaking discoveries. These include the relative independence of blood flow and oxygen consumption during changes in brain activity, which provided the physiological basis of fMRI, as well the discovery of the well known Default Mode Network.Fox, M. D., Snyder, A. Z., Vincent, J. L., Corbetta, M., Van Essen, D. C., & Raichle, M. E. (2005). The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proceedings of the National Academy of Sciences of the United States of America, 102(27), 9673-9678. Connectivity Functional Functional connectivity is the connectivity between brain regions that are share functional properties. More specifically, it can be defined as the temporal correlation between spatially remote neurophysiological events, expressed as deviation from statistical independence across these events in distributed neuronal groups and areas.Biswal, B. B., VanKylen, J., & Hyde, J. S. (1997). Simultaneous assessment of flow and BOLD signals in resting-state functional connectivity maps. Nmr in Biomedicine, 10(4-5), 165-170. This applies to both resting state and task-state studies. While functional connectivity can refer to correlations across subjects, runs, blocks, trials, or individual time points, resting state functional connectivity focuses on connectivity assessed across individual BOLD time points during resting conditions.Friston, K. (2009). Causal Modelling and Brain Connectivity in Functional Magnetic Resonance Imaging. Material. Plos Biology, 7(2), 220-225. Functional connectivity MRI (fcMRI), which can include resting state fMRI and task-based MRI, might someday help provide more definitive diagnoses for mental health disorders such as bipolar disorder and may also aid in understanding the development and progression of post-traumatic stress disorder as well as evaluate the effect of treatment.Smith, S. M. (2012). The future of FMRI connectivity. Neuroimage, 62(2), 1257-1266. Structural The connectivity of brain regions that are physically or anatomically attached to one another is referred to as structural connectivity. Regions of the brain do not have to be structurally connected to have functional connectivity, and a structural connection does not necessarily signify a functional link.Biswal, B. B., Mennes, M., Zuo, X. N., Gohel, S., Kelly, C., Smith, S. M., et al. (2010). Toward discovery science of human brain function. Proc Natl Acad Sci U S A, 107(10), 4734-4739. Several initiatives such as the Human Connectome Project to try and build a connectome or a neural connectivity map that will shed light on the anatomical as well as functional connectivity within the healthy human brain.Van Essen, D. C., & Ugurbil, K. (2012). The future of the human connectome. Review. Neuroimage, 62(2), 1299-1310. Networks Default mode network :The default mode network (DMN) is a network of brain regions that are active when an individual is awake and at rest. The default mode network is an interconnected and anatomically defined brain system that preferentially activates when individuals focus on internal tasks such as daydreaming, envisioning the future, retrieving memories, and gauging others' perspectives.Greicius, M. D., Krasnow, B., Reiss, A. L., & Menon, V. (2003). Functional connectivity in the resting brain: A network analysis of the default mode hypothesis. Proceedings of the National Academy of Sciences of the United States of America, 100(1), 253-258. It is negatively correlated with brain systems that focus on external visual signals. It is one of the most studied networks present during resting state and is one of the most easily visualized networks.Buckner, R. L. (2012). The serendipitous discovery of the brain's default network. Neuroimage, 62(2), 1137-1145. Other resting state networks :Depending on the method of resting state analysis, functional connectivity studies have reported a number of neural networks that result to be strongly functionally connected during rest. The key networks, also referred as components, which are more frequently reported include: the DMN, the sensory/motor component, the executive control component, up to three different visual components, two lateralized frontal/parietal components, the auditory component and the temporal/parietal component.Moussa, M. N., Steen, M. R., Laurienti, P. J., & Hayasaka, S. (2012). Consistency of network modules in resting-state FMRI connectome data. PLoS One, 7(8), e44428. As already reported, these resting-state networks consist of anatomically separated, but functionally connected regions displaying a high level of correlated BOLD signal activity. These networks are found to be quite consistent across studies, despite differences in the data acquisition and analysis techniques.Lee, M. H., Hacker, C. D., Snyder, A. Z., Corbetta, M., Zhang, D. Y., Leuthardt, E. C., et al. (2012). Clustering of Resting State Networks. PLoS One, 7(7). Importantly, most of these resting-state components represent known functional networks, that is, regions that are known to share and support cognitive functions. Analyzing Data Processing data Many programs exist for the processing of resting state fMRI data. Some of the most commonly used programs for processing and analyzing fMRI data include SPM, Afni and FSL (esp. for ICA). Common methods There are many methods of both acquiring and processing rsfMRI data, yet there are two methods of analysis that have become the most popular methods for the analysis of functional connectivity in the brain. Independent component analysis :Independent component analysis (ICA) is a useful statistical approach in the detection of resting state networks. ICA separates a signal into non-overlapping spatial and time components. It is highly data-driven and allows for better removal of noisy components of the signal (motion, scanner drift, etc). It also has been shown to reliably extract default mode network as well as many other networks with very high consistency.Beckmann, C. F., DeLuca, M., Devlin, J. T., & Smith, S. M. (2005). Investigations into resting-state connectivity using independent component analysis. Philosophical Transactions of the Royal Society B-Biological Sciences, 360(1457), 1001-1013. Seed-based/Region of interest :Another method of observing networks and connectivity in the brain is the Seed-Based or region of interest (ROI) method of analysis. In this case, signal from only a certain voxel or cluster of voxels known as the seed or ROI are used to calculate correlations with other voxels of the brain. This provides a much more precise and detailed look at specific connectivity in brain areas of interest.Margulies, D. S., Kelly, A. M. C., Uddin, L. Q., Biswal, B. B., Castellanos, F. X., & Milham, M. P. (2007). Mapping the functional connectivity of anterior cingulate cortex. Neuroimage, 37(2), 579-588.Van Dijk KRA, Hedden T, Venkataraman A, Evans KC, Lazar SW, and Buckner RL (2010) Intrinsic Functional Connectivity As a Tool For Human Connectomics: Theory, Properties, and Optimization. Journal of Neurophysiology. 103: 297-321. Other methods for characterizing resting-state networks include partial correlation, coherence and partial coherence, phase relationships, clustering, and graph theory.Chang, C., & Glover, G. H. (2010). Time-frequency dynamics of resting-state brain connectivity measured with fMRI. Neuroimage, 50(1), 81-98.Faria, A. V., Joel, S. E., Zhang, Y. J., Oishi, K., van Zjil, P. C. M., Miller, M. I., et al. (2012). Atlas-based analysis of resting-state functional connectivity: Evaluation for reproducibility and multi-modal anatomy-function correlation studies. Neuroimage, 61(3), 613-621. Combining imaging techniques fMRI with EEG Many imaging experts feel that in order to obtain the best combination of spatial and temporal information from brain activity, both fMRI as well as electroencephalography (EEG) should be used simultaneously. This dual technique combines the EEG’s well documented ability to characterize certain brain states with high temporal resolution and to reveal pathological patterns, with fMRI’s (more recently discovered and less well understood) ability to image blood dynamics through the entire brain with high spatial resolution. Up to now, EEG-fMRI has been mainly seen as an fMRI technique in which the synchronously acquired EEG is used to characterize brain activity (‘brain state’) across time allowing to map (through statistical parametric mapping, for example) the associated haemodynamic changes.Majeed, W., Magnuson, M., & Keilholz, S. D. (2009). Spatiotemporal Dynamics of Low Frequency Fluctuations in BOLD fMRI of the Rat. Journal of Magnetic Resonance Imaging, 30(2), 384-393. The clinical value of these findings is the subject of ongoing investigations, but recent researches suggest an acceptable reliability for EEG-fMRI studies and better sensitivity in higher field scanner. Outside the field of epilepsy, EEG-fMRI has been used to study event-related (triggered by external stimuli) brain responses and provided important new insights into baseline brain activity in during resting wakefulness and sleep.Keilholz, S. D., Magnuson, M., & Thompson, G. (2010). Evaluation of data-driven network analysis approaches for functional connectivity MRI. Brain Structure & Function, 215(2), 129-140. fMRI with TMS Transcranial magnetic stimulation (TMS) uses small and relatively precise magnetic fields to stimulate regions of the cortex without dangerous invasive procedures. When these magnetic fields stimulate an area of the cortex, focal blood flow increases at the site of stimulation as well as at distant sites anatomically connected to the stimulated location. Positron emission tomography (PET) can then be used to image the brain and changes in blood flow and results show very similar regions of connectivity confirming networks found in fMRI studies and TMS can also be used to support and provide more detailed information on the connected regions.Fox, M. D., Halko, M. A., Eldaief, M. C., & Pascual-Leone, A. (2012). Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS). Neuroimage, 62(4), 2232-2243. Potential pitfalls Potential pitfalls when using rsfMRI to determine functional network integrity are contamination of the BOLD signal by the before-mentioned sources of physiological noise such as heart rate, respiration ,Birn, R.M., Diamond, J.B., Smith, M.A., Bandettini, P.A., 2006. Separating respiratory-variation-related fluctuations from neuronal-activity-related fluctuations in fMRI. Neuroimage 31, 1536-1548. Chang, C., Glover, G.H., 2009. Relationship between respiration, end-tidal CO(2), and BOLD signals in resting-state fMRI. Neuroimage. and head motion.Van Dijk, K.R.A., Sabuncu, M.R., Buckner, R.L., 2012. The influence of head motion on intrinsic functional connectivity MRI. Neuroimage 59, 431-438.Power, J.D., Barnes, K.A., Snyder, A.Z., Schlaggar, B.L., Petersen, S.E., 2012. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage 59, 2142-2154.Satterthwaite, T.D., Wolf, D.H., Loughead, J., Ruparel, K., Elliott, M.A., Hakonarson, H., Gur, R.C., Gur, R.E., 2012. Impact of in-scanner head motion on multiple measures of functional connectivity: relevance for studies of neurodevelopment in youth. Neuroimage 60, 623-632. It is crucial that investigators that apply rsfMRI are aware of these confounding factors since they often bias results in studies where patients are compared to healthy controls in the direction of hypothesized effects (e.g. one might find lower coherence in the default network in the patient group, while the patient groups also moved more during the scan). Current and future applications Research using resting state fMRI has already proven to have many useful clinical applications, including use in the assessment of many different diseases and mental disorders.Holtbernd, F., & Eidelberg, D. (2012). Functional brain networks in movement disorders: recent advances. Current Opinion in Neurology, 25(4), p. 392-401. Disease Condition and Changes in Resting State Functional Connectivity * Alzheimer's disease: decreased connectivityLi, R., Wu, X., Chen, K., Fleisher, A. S., Reiman, E. M., & Yao, L. (2012). Alterations of Directional Connectivity among Resting-State Networks in Alzheimer Disease. AJNR Am J Neuroradiol. * Autism: altered connectivityMüller, R-A., Shih, P., Keehn, B., Deyoe, J., Leyden, K., & Shukla, D. (2011). Underconnected but how? A survey of functional connectivity MRI studies in autism spectrum disorders. Cerebral Cortex, 21(10), 2233–2243. * Depression: increased connectivityHulvershorn, L. A., Cullen, K., & Anand, A. (2011). Toward dysfunctional connectivity: a review of neuroimaging findings in pediatric major depressive disorder. Brain Imaging Behav, 5(4), 307-328. * Schizophrenia: disrupted networksVenkataraman, A., Whitford, T. J., Westin, C. F., Golland, P., & Kubicki, M. (2012). Whole brain resting state functional connectivity abnormalities in schizophrenia. Schizophrenia Research, 139(1-3), 7-12. * Attention deficit hyperactivity disorder (ADHD): Altered "small networks" and Thalamus changesUddin, L. Q., Kelly, A. M. C., Biswal, B. B., Margulies, D. S., Shehzad, Z., Shaw, D., et al. (2008). Network homogeneity reveals decreased integrity of default-mode network in ADHD. Journal of Neuroscience Methods, 169(1), 249-254. * Aging brain: disruption of brain systems and motor network * Epilepsy: disruption and decrease/increase in connectivityWurina, Zang, Y. F., & Zhao, S. G. (2012). Resting-state fMRI studies in epilepsy. Neuroscience Bulletin, 28(4), 449-455. * Parkinson's disease: altered connectivityTessitore, A., Amboni, M., Esposito, F., Russo, A., Picillo, M., Marcuccio, L., et al. (2012). Resting-state brain connectivity in patients with Parkinson's disease and freezing of gait. Parkinsonism & Related Disorders, 18(6), 781-787. * Obsessive Compulsive Disorder:increase/decrease in connectivityLi, P., Li, S. F., Dong, Z. Y., Luo, J., Han, H. Y., Xiong, H. F., et al. (2012). Altered resting state functional connectivity patterns of the anterior prefrontal cortex in obsessive-compulsive disorder. Neuroreport, 23(11), 681-686. * Pain Disorder: altered connectivityOtti A, Guendel H, Wohlschlager A, Zimmer C, Noll-Hussong M. Frequency shifts in the anterior default mode network and the salience network in chronic pain disorder. BMC Psychiatry. 2013;13:84.Otti A, Guendel H, Henningsen P, Zimmer C, Wohlschlaeger AM, Noll-Hussong M. Functional network connectivity of pain-related resting state networks in somatoform pain disorder: an exploratory fMRI study. J Psychiatry Neurosci. Support, Non-U.S. Gov't. 2013 Jan;38(1):57-65. Other types of current and future clinical applications for resting state fMRI include identifying group differences in brain disease, obtaining diagnostic and prognostic information, longitudinal studies and treatment effects, clustering in heterogeneous disease states, and pre-operative mapping and targeting intervention.Fox, M. D., & Greicius, M. (2010). Clinical applications of resting state functional connectivity. Front Syst Neurosci, 4, 19. See also * Issues in fMRI * Medical image computing References Category:Magnetic resonance imaging Category:Medical imaging Category:Neuroscience